Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis

Johanna Tommiska, Johanna Känsäkoski, Lasse Skibsbye, Kirsi Vaaralahti, Xiaonan Liu, Emily J. Lodge, Chuyi Tang, Lei Yuan, Rainer Fagerholm, Jørgen K. Kanters, Päivi Lahermo, Mari Kaunisto, Riikka Keski-Filppula, Sanna Vuoristo, Kristiina Pulli, Tapani Ebeling, Leena Valanne, Eeva-Marja Sankila, Sirpa Kivirikko, Mitja Lääperi, Filippo Casoni, Paolo Giacobini, Franziska Phan-Hug, Tal Buki, Manuel Tena-Sempere, Nelly Pitteloud, Riitta Veijola, Marita Lipsanen-Nyman, Kari Kaunisto, Patrice Mollard, Cynthia L. Andoniadou, Joel A. Hirsch, Markku Varjosalo, Thomas Jespersen and Taneli Raivio ()
Additional contact information
Johanna Tommiska: University of Helsinki
Johanna Känsäkoski: University of Helsinki
Lasse Skibsbye: University of Copenhagen
Kirsi Vaaralahti: University of Helsinki
Xiaonan Liu: University of Helsinki
Emily J. Lodge: King’s College London
Chuyi Tang: University of Copenhagen
Lei Yuan: University of Copenhagen
Rainer Fagerholm: University of Helsinki
Jørgen K. Kanters: University of Copenhagen
Päivi Lahermo: University of Helsinki
Mari Kaunisto: University of Helsinki
Riikka Keski-Filppula: Oulu University Hospital
Sanna Vuoristo: University of Helsinki
Kristiina Pulli: University of Helsinki
Tapani Ebeling: Oulu University Hospital, Finland and Research Unit of Internal Medicine, University of Oulu
Leena Valanne: Helsinki Medical Imaging Center, HUCH
Eeva-Marja Sankila: HUCH
Sirpa Kivirikko: HUCH
Mitja Lääperi: University of Helsinki
Filippo Casoni: Development and Plasticity of the Neuroendocrine Brain
Paolo Giacobini: Development and Plasticity of the Neuroendocrine Brain
Franziska Phan-Hug: University Hospital Lausanne (CHUV)
Tal Buki: George S. Wise Faculty of Life Sciences, Institute of Structural Biology
Manuel Tena-Sempere: Physiology and Immunology, University of Córdoba
Nelly Pitteloud: University Hospital Lausanne (CHUV)
Riitta Veijola: Oulu University Hospital
Marita Lipsanen-Nyman: Helsinki University Central Hospital (HUCH)
Kari Kaunisto: Oulu University Hospital
Patrice Mollard: IGF, CNRS, INSERM, Univ. Montpellier
Cynthia L. Andoniadou: King’s College London
Joel A. Hirsch: George S. Wise Faculty of Life Sciences, Institute of Structural Biology
Markku Varjosalo: University of Helsinki
Thomas Jespersen: University of Copenhagen
Taneli Raivio: University of Helsinki

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations.

Date: 2017
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DOI: 10.1038/s41467-017-01429-z

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